This HIVRAD program merges the complementary expertise of leading HIV-1 researchers in order to provide a fundamental advance towards an HIV-1 vaccine than can elicit broadly neutralizing antibodies (NAbs). This innovative program comprises two Research Projects: HIV-1 Env Vaccine Design (Dr. John Moore, Cornell University) and HIV-1 Trimer Crystallography (Dr. Ian Wilson, The Scripps Research Institute). The Projects are supported by scientific and administrative Cores (Dr. William Olson, Progenies Pharmaceuticals). This program leverages our recent successes in generating stable, proteolytically mature gp140 trimers (SOSIP gp140s) that mimic virion-associated Env in topology and antigenicity. As immunogens, SOSIP trimers have proven to be superior to matched gp120s in eliciting NAbs in animals. In the HIVRAD, the SOSIP template will be tailored for structural studies and for further improvements in immunogenicity in animals. Our overall goals of the HIVRAD are reflected in three major milestones: 1) determine the structure of cleaved Env trimers at <4A resolution, 2) demonstrate methods to overcome HIV-1 Env's immunosuppressive properties, and 3) identify a SOSIP trimer vaccine that elicits heterologous neutralization of diverse HIV-1 isolates. Given the present rudimentary knowledge of trimer structure, an atomic-level view has the potential to spur development of a new generation of rationally designed Env vaccines, and our preliminary studies on crystallizing SOSIP trimers provide high enthusiasm and guarded optimism for success. Parallel studies will evaluate SOSIP trimers that have been modified so as to improve presentation of NAb epitopes and/or remove Env immunosuppressive features. Animal immunogenicity studies will be complemented with in vitro studies that compare modified and unmodified forms of Env for their ability to elicit immunosuppressive responses in human dendritic cells. In addition to the primary Projects and Cores, the HIVRAD includes additional leading academic and corporate collaborators who lend specialized expertise in the areas of vaccine delivery (Aldevron, Inc.), NAb analyses (Monogram Biosciences), NAb specificity analyses (Dr. James Binley), in vitro immunogenicity studies (VaxDesign), and exploratory immunogenetics (Dr. Sunil Ahuja). Our shared goal is to overcome key structural and immunological challenges to developing a successful Env-based HIV-1 vaccine.